Department
of Clinical Neuroscience, College of Medicine, King Faisal University-Al Hassa,
Kingdom of Saudi Arabia

Introduction

Sickle
cell disease (SCD) is a group of inherited red blood cell disorders
characterized by the presence of abnormal hemoglobin. The clinical manifestations
are diverse and may include vaso-occlusive, hematological and infectious crises
[1,2]. SCD is present throughout Saudi
Arabia; particularly common in the eastern and southern provinces: Qatif (eastern
region) 17.0 %, Gizan (southern region), 10.3%, Ula (Northern region) 8.1
% and Mecca (western region) 2.5 % [3]. Increased life
expectancy due to recent medical advances has increased the need to understand
more fully the quality of life (QoL) in patients with SCD and factors
predicting disease adaptation [4,5].
QoL measures are used not only to assess the psychosocial impact of the disease
but also in evaluating the efficacy of medical care [6-9]
and it is the goal of health care providers to enhance treatment outcome and
restore comfort and well-being of their patients [10]. In
particular, health related quality of life (HRQoL) assessments in adolescents
with chronic disease condition facilitate doctor–patient communication, they
point to areas where patients may experience serious problems, they can be used
as diagnostic tools for problem-oriented follow–up care, and the data are
strong predictors of survival [11].

Previous
research indicated that patients with SCD experienced a lower HRQoL compared to
the general adult's population [12] Dampier et al [13] found that children with SCD as well as their parents
scored significantly lower on several HRQoL domains including; general
physical, motor and independent daily functioning. Trzepacz et al [14] identified deteriorations in social and school competence
for children with SCD, compared to healthy peers, but they did not find an
association with disease severity as measured by sickle cell genotype. A number
of disease-related factors have been found to affect HRQoL in pediatric SCD.
Several studies that examined the influence of various determinants including
the role of socio-demographics, disease severity and the presence of
complications on HRQoL in SCD patients were carried out in the developed
countries [12,13,15,16] while in the developing countries similar studies do not
exist. Furthermore, adolescent health is a relatively unexplored component of
public health in many developing countries [17,18].

Researches
on chronic diseases have indicated that HRQoL varies according to
socio-demographic characteristics such as income level, educational status,
ethnicity, occupational status, age, and gender, with the disadvantaged groups
typically reporting lower HRQoL. This association has been reported for many
chronic conditions including cancer [19], HIV infection [20], renal disease [21], and sickle cell
disease [15]. Also, studies involving healthy populations have
indicated that there is an inverse association between children’s HRQoL and
family variables such as low parental education, socio-economic status (SES) [22-24] with low family income contributing to caregiver
distress in families of children with chronic conditions [25].
Also, Simon et al [26] reported that HRQoL is poorest for
children and youth in lower socioeconomic status groups, those with access
barriers, adolescents compared with children, and individuals with medical
conditions.

Studies
on the relationship of socio-economic variables and the HRQoL in patients with
SCD revealed conflicting results. Van den Tweel et al [27]
indicated that children of parents with low educational level perceived a
significantly better HRQoL. This phenomenon is difficult to explain, since
previous research mainly pointed out that high quality of life scores were
related to high parental education, or that education had no effect at all [11,28]. Also, previous research has
shown that children with low socioeconomic status (SES) functioned worse than
children from middle SES backgrounds [29].

Limitations
in HRQoL have been documented consistently for youth with SCD, [15,30,31] particularly as children
move into adolescence and young adulthood [32,33]. Sickle cell pain, a common manifestation that is
recurrent, acute, and unpredictable, may be the most important disease
complication associated with deterioration in physical and psychosocial domains
of HRQoL [15,34,35].
Palermo et al [32] reported that sickle cell complications
(including pain), in addition to child age and gender, are central to physical
but not psychosocial HRQoL in their sample of adolescents with SCD. Yet,
Panepinto and colleagues [36] found that only pain, no
other SCD complications, was associated with the deterioration in the physical
domain of HRQoL but not the psychosocial.

Although
pain and other sickle cell complications show an association with decrements in
engagement in physical activities and in physical domains of HRQoL,
documentation of a significant association of pain with psychosocial domains of
HRQoL are not consistent [37]. Recently, Brandow et al. [38] examined HRQoL in children with SCD specifically in relation
to painful events at presentation to the emergency room and seven days
post-discharge. They found that painful events diminished all domains of HRQoL
and that these domains improve after the pain resolves. If these variables
(socio-demographic and disease related complications) are crucial in
determining HRQoL among adolescent patients with SCD, by controlling of these
factors, we may better support them with successful transition to adulthood and
with less burden on healthcare services [39]. We
specifically hypothesized that adolescents with SCD would have decreased mean
scores along the different subscales of the HRQoL measure compared to
adolescents without SCD. We also predicted that certain demographic factors
(increasing age, gender, low socio-economic status) would be related to HRQoL
with males and adolescents from lower SES backgrounds reporting lower quality
of life. Additionally, we predicted that adolescents with SCD who experienced
disease-related complications, frequent pain episodes, and greater health care
utilization would report lower quality of life than adolescents with SCD who
did not report these factors. The objective of this study were to assess the
impairment of the different domains of HRQoL among Saudi adolescents with SCD
compared to healthy peers and to define the relationship between
socio-demographic variables, the presence of diseases related complications
with the degree of impairment in HRQoL.

Methods

Settings

This
study was carried out in Hematology clinics of two general hospitals; King Fahd
Hospital in Hofuf and Al Qatif General Hospital in Al Qatif city, Eastern
Province, Saudi Arabia. Both hospitals provide secondary level of care and
serve about one and half million populations. Adolescents with SCD and their
counterparts were selected from these hospitals.

Patients

Adolescents with SCD were recruited out of those attending Hematology clinics
at both hospitals attending for routine assessment, follow-up and management. Inclusion
criteria for adolescents with SCD included: Both genders with age ranged from
14 to 18 years of indigenous Saudi nationality and free form acute or chronic
illnesses, handicapping conditions, and cognitive problems (Data were affirmed through
the hematology consultants at the clinics and review of medical
records). A total of 285 adolescents with SCD were eligible from both
hospitals (King Fahd n=132) and Al Qatif (n=153) of which 188 were males and 97
females.

Personal
contact and phone calls were used to approach patients' parents/legal guardians
to recruit the eligible SCD adolescents. Out of those approached;
parents/guardians of 136 males and 44 females agreed to participate. There was
no significant difference in relation to the socioeconomic and disease status
of those refused to participate compared to the rest of the sample as revealed
from reviewing of available hospital records. Higher refusal was recorded among
parents of females with SCD, as the response rate was 45.4% compared to males
(72.3%).

Adolescents
without SCD: Following the selection of SCD patients, we employed a
non-probability sampling method to recruit healthy adolescents for the sake of
comparison. Attendees from the two hospitals within the same age range,
nationality, and gender and accompanying their relatives at various outpatients
clinics.

Exclusion
criteria included: Having any chronic physical illnesses or cognitive problems,
diagnosed with any hemoglobinopathies or having a positive family history of
hemolytic blood diseases and with positive history of acute, chronic illnesses
or health related problems within the last four weeks of data collection.

Out
of 361 (253 males and 108 females) subjects approached, parents' (guardians) of
202 adolescents (152 males and 50 females) agreed to participate. The existence
of a significant difference in relation to the socio-demographic (other than
age and gender) of this group was not confirmed due to lack of information.

Permissions
were obtained from hospitals' authorities as well as our institution after
approval of the proposal and data collection tools. Prior orientation of
parents/legal guardians was carried out before obtaining of an informed consent
form with emphasis on the right of the subject of non-participation. Assents
forms were obtained from adolescents after receiving proper orientation. Data
confidentiality was maintained all through the study.

Measurements

Socio-demographic
data were collected through a personal interview with parents/legal guardians
of adolescents with SCD and the comparison group using a structured
questionnaire to elicit information regarding socio-demographic characteristics
including age in years, residence, educational status of parents and subjects
and monthly family income in Saudi Riyals. The interviews were carried out on
the same day of attending the clinics in the afternoon in a separate room away
from the busy clinics by trained interviewers (medical graduates) under the
supervision of the investigators.

Disease
related data SCD were obtained through available medical records and confirmed
by the attending hematology consultants, including: disease genotype,
percentage of fetal hemoglobin, SCD related complications and their nature,
frequency of painful episodes in the last month, and frequency of emergency
hospital admissions in the last year.

Health
Related Quality of Life: Following parents/guardians interview, HRQoL was
assessed through self-reporting of the Short-Form (SF-36) 'version 2.0' [40]. All participants were asked to fill the questionnaire;
assistance was provided when necessary for those with reading and/or writing
difficulties.

The SF-36 is one of the most common, generic measures of HRQoL and has been
employed in numerous studies involving chronic illnesses. The SF-36
questionnaire was designed in the 80s to provide a generic measure of HRQoL of
those aged 14 years and older [41]. The translated Arabic
version of the SF-36 [42] which has shown reliability with
Arabic-speaking population was employed to evaluate HRQoL.

SF-36
is made up of eight subscales, each evaluating a different domain of HRQoL;
physical functioning, physical role functioning, bodily pain, general health,
vitality and energy, social functioning, role emotional and mental (emotional)
health. Subscale scores are calculated from 35 out of the 36 items (one item
about self-reported health transition is not included in the scores). SF-36
yielding score values from 0 to 100, higher scores indicate better quality of
life. Alpha coefficients were calculated to estimate the internal consistency
reliability of each SF-36 subscale. Alpha coefficients were high
in the domains of physical functioning, role physical and role emotional among
both groups of adolescents. Bodily pain, vitality, emotional well-being and
social functioning showed a coefficient of less than .8 while, general health
showed the least reliability coefficient among adolescents with
SCD.

Data
analysis

With
inclusion of 131 subjects in each group we had more than 90% [43]
power to detect 8.0 [12,16], standard
deviations difference with precision of ±3.0 along the eight subscales of HRQoL
between adolescents with SCD and their comparable group of adolescents without
SCD at an alpha level of 0.05 (two sided). Considering a potential refusal rate
of 30%, the total sample size would be 170 subjects in each group.

Data
were processed and analyzed using SPSS version 16.0 (SPSS Inc. Chicago IL).
Analysis was carried out along the SF-36 scoring protocol. Results obtained from
HRQoL domains were expressed in mean and standard deviation. Both descriptive
and inferential statistics were applied as appropriate.

Statistical
tests of significance including t-test for continuous variables, Chi-square and
Fisher Exact were used for categorical data to detect difference between
groups. Effect sizes in the form of Cohen's d [44] were
calculated as the difference between the means, divided by standard deviation
of either group when the variances of the two groups are homogeneous, in our
case we employed the pooled standard deviation to calculate the effect size
(equals to the root mean square of the two standard deviations for adolescents
with and without SCD).

The
interpretation based on the average percentile standing of the average of
adolescents without SCD relative to the average of adolescents with SCD.
Multivariate linear regression models were generated to define the association
between socio-demographics and SCD related variables (independent) to the mean
scores along HRQoL domains (dependent), standardized β coefficients and P
value were reported for each model. P value of < 0.05 was applied as a level
of significance.

Results

Socio-demographics

Adolescents
with SCD (n=180, 136 males and 44 females) and a comparable group of
adolescents without SCD (n=202, 152 males and 50 females) their age ranged from
14 to 18 years with a mean of 16.9± 2.5 years, the mean age of adolescents with
SCD was 16.8±3.6 years and the age of their counterpart was 16.9±1.7 years.

Adolescents
with SCD have a lower socio-demographic profile in terms of parental
educational status and family income compared to adolescents without SCD but
without statistical difference (Table 1).

Adolescents
with SCD showed a significant educational delay in terms of excessive failing
and school retention while adolescents without SCD was significantly better;
15.0% of adolescents with SCD demonstrated delay (excessively retained in
relation to their comparable peers) in the primary (elementary=up to grade 6)
education compared to only 2.0% among adolescents without SCD, and 71/81
(87.7%) of adolescents with SCD in the preparatory stage (intermediate= up to
grade 9) were delayed compared to 8/39 (21.1%) among adolescents without SCD.
This delay was attributed by the parents due to excessive absenteeism from
schools in response to frequent hospitalization, emergency admissions, and
appointments for checkups.

Genotypes
and disease-related complications

Table 1) displays the encountered SCD genotypes and SCD related complications among
the included adolescent with SCD. Painful episodes in the last month were
recorded in 56.7 % of cases, and the need for emergency hospital admission
during the last year was found in 25.5% of cases. All SCD patients were on
Hydroxyurea (HU) therapy, recorded fetal hemoglobin level (in 167/180 cases)
had a mean of 13.1±6.4 % (median of 12.5%) with an interquartile range of
19.0%.

Health
Related Quality Of Life

Domains
of HRQoL were significantly deteriorated in adolescents with SCD (Table 2)). The
mean scores of adolescents without SCD were above the 93rd
percentiles of adolescents with SCD in role physical and general health
domains, above the 97th percentiles in the domain of bodily pain,
higher than 79th percentiles of adolescents with SCD in physical
functioning, and 76th percentile in the social functioning domain.

Male
adolescents with SCD scored significantly worse than males without SCD in all
domains of HRQoL (Table 3)). Male adolescents without SCD demonstrated mean
scores above the 96th percentiles of adolescents with SCD in role
physical and bodily pain domains, above the 93rd percentiles in
general health, above the 79th percentiles of physical functioning
domains. Role emotional and emotional well-being domains showed less effect
sizes, the mean scores among adolescents without SCD were above the 58th
and 66th percentiles of the mean of adolescents with SCD
respectively.

Adolescent
females with SCD achieved lower scores than females without SCD in role
emotional, vitality, emotional well-being and social functioning domains but
without statistical significance. Adolescent females without SCD had mean
scores in the physical functioning and bodily pain above the 95th
percentiles of females with SCD, general health scores was above the 90th
percentiles and role physical mean scores was above 76th percentiles
of adolescents with SCD.

Adolescent
females with SCD scored higher than females without SCD in role emotional and
vitality, adolescent females with SCD achieved mean scores above the 58th
percentiles of females without SCD in both domains (Table 3)).

Male
adolescents with SCD achieved higher scores in the domains of physical
functioning, bodily pains and social functioning compared to female patients
but without statistical difference. Emotional well-being scores were
significantly higher among male adolescents with SCD compared to female patients (Table 3)).

The
mean scores of male adolescents with SCD in emotional well-being domain were
above the 66th percentiles for females with SCD. Female adolescents
with SCD had higher scores in role physical and role emotional domains compared
to males with SCD but without significant difference.

Adolescents
without SCD complications had mean scores above the 69th percentiles
of those with complications in the domains of role physical and role emotional,
above the 62nd percentiles in physical functioning, general health,
and emotional well-being domains of the average scores for those with SCD
complications (Table 4)).

Multivariate
linear regression models showed that all domains of HRQoL were negatively
associated with increasing of age of the adolescent with SCD especially in
domains of energy, emotional wellbeing, social function and general health (Table 5).

Female
gender was negatively associated with scores in the domain of emotional
wellbeing. Urban residence was positively associated with higher vitality score
and higher family income was associated with increase in scores of physical
functioning domain. Frequent hospital emergency admissions were associated with
lower scores in almost all subscales especially physical, role physical and
emotional well-being domains.

Discussion

To
the authors' knowledge, this is the first study to assess HRQoL in adolescent
patients with SCD in an Arabic community. The data reported here showed that
adolescents with SCD experiencing impairment in HRQoL when compared with their
healthy peers. The smallest differences between adolescent controls and SCD
group were evident in the role emotional and emotional wellbeing domains.
Similar to our findings, McClish et al [12] reported that
young adult with SCD experienced a poor HRQoL except for mental health. Patel
and Palham [45] reported that Indian children with SCD
experienced a poor HRQoL along physical, psychosocial and cognitive domains.

It
has been suggested that people with chronic diseases may report good
psychological well-being as a result of increased social support,
religiousness, lack of other stressors, or due to the presence of a
"response shift" associated with coping and managing of their illness
[46].

In Saudi culture, several factors may explain the
process of psychological coping among adolescents with SCD. First, the extended
family pattern in Saudi Arabia; family provide people suffering from anxiety
the presence of ‘‘safe persons’’ around them and hide active symptoms of
anxiety, maintaining them functional in a compensatory behavior [47]. Adolescence is typically a period of rapid physical, cognitive
and psychosocial change that takes place in the context of shifting
relationships and roles within the family [48]. The Family
Adjustment and Adaptation Response (FAAR) model highlights how adaptation to
chronic childhood illness is explained in the balance of family demands
(stressors from individual, family, and community sources) as well as family
resources such as positive parent-child relationships, family functioning, and
active coping and positive beliefs/attitudes [49]. Second,
the health care management policy in Saudi Arabia, where the services are free
of charge and all SCD patients received Hydroxyurea (HU) which can improve some
domains of HRQoL including social function, general health perception and pain
recall [34].

Finally,
recorded fetal hemoglobin level in this study had a mean of 13.1±6.4 % (median
of 12.5%) with an interquartile range of 19.0%, higher than that reported in
patients with African haplotypes [50]. Pearson [51] and Perrine et al. [50] found that
serious complications (i.e. jaundice, splenectomy, and hematuria) occurred in only
6% to 25% of Saudi patients compared to North American Blacks.

Despite
the increased attention paid to determine factors that affect QoL in SCD [13,45,52] fewer studies
addressed the influence of gender. In our study, female participants was less
and we speculated that this may be due to the disease associated stigma and
fear of disclosure as many females with SCD preferred to receive disease
management in private health facilities where more confidentiality is provided.

Despite increased attention being paid to determine factors that affect the
quality of life in SCD, there are few studies that address the influence of
gender. Some studies suggested that females have a poorer quality of life than
their male counterparts [29] while, others did not reveal
gender difference [30]. There is also suggestion that
gender may influence the way adolescents' perceiving of health [31].

Among
our adolescents with SCD, gender differences in HRQoL existed between males and
females. Adolescent girls with SCD achieved significantly lower scores in
physical functioning, role physical, bodily pain and general health domains.
Ironically, they have higher score along social function and emotional
well-being compared to their healthy controls.

Studies dealt with behavior adjustment in children with chronic diseases showed
conflicting results in relation to the effect of gender. Zandieh et al [53] found that QoL in Iranian boys with bronchial asthma were
more deteriorated than females.

While in Swedish study, Hanberger et al. [54] reported
lower Generic HRQoL and Diabetes-specific HRQoL mean scores in adolescent girls
with type 1 diabetes mellitus than boys. HRQoL did not show a significant
relationship with SCD genotype. The relationship between SCD genotype, disease
severity and HRQoL may have been mediated by other variables, particularly
disease-related complications. In addition, some of HRQoL subscales were
significantly deteriorated with increasing hospitalization frequency. Anie et
al [52] found a relationship between pain and some HRQoL
domains 'physical, social functions, mental and general health' while others [12] found no significant association with health care
utilization measures.

In
this study nearly all domains of HRQoL were negatively associated with
increasing age of adolescent with SCD especially energy, emotional well-being,
social functioning and general health domain. Baskin et al. [31]
found that there was an interactive effect between age and disease adjustment
which become more problematic as SCD patient mature with additional
difficulties as the disease worsens in severity (e.g., increase in
vaso-oclusive episodes). Furthermore, physical manifestations of SCD notably in
the form of abnormal sexual and physical development, as evidenced by delayed
growth and puberty, priapism and short stature may add more difficulties to the
growing patient.

Adolescents with SCD in our study reported significant educational delay due to
frequent hospitalization, emergency admissions, and appointments for checkup.
This is consistent with other studies reported that adolescents with SCD
commonly experience role limitation due to emotional problems with subsequent
educational problems [45,55].

Rural
residence was a significant negative predictor for vitality and pain of HRQoL
subscales. There are limited studies on rural/ urban differences in QoL among patients
with SCD. Telfair et al [55] have shown that rural
patients had lower health service access and utilization with lower physical
functioning. Future researches should investigate the role the differential
levels of social support, coping styles, and perceptions of illness in
urban-rural differences in QoL among SCD patients.

Another
risk factor for lower HRQoL among our patients was the low family income. Saudi
youth with lower socioeconomic standard were more likely to have lowered
physical functioning scores. Children living under poorer economic conditions
are more prone to anxiety, depression and negative thinking with potential
exaggeration with adolescents with SCD through increasing exposure to stressful
experiences and decreasing psychological and social coping resources [56]. Panepinto et al [57] have found a
significant negative effect of poverty and disease severity on the HRQoL among
pediatric patients and it was chiefly affecting the physical functions of the
included children with SCD.

Health care providers have limited ability to improve the poverty status of the
affected patients but improvement of disease status and prevention of disease
complications may help in improvement of their well-being especially physical
wellbeing [2].

The
combined effects of SCD-related pain and low socioeconomic status [56] on school attendance may limit opportunities for physical
education with subsequent reduction of physical HRQoL.

Socio-demographic
variables were found to adversely affect the HRQoL in patients with chronic
conditions as reveled by several cross-sectional studies, yet prospective
studies are required to better elucidate the predictive value of family
variables. Barakat et al [57] found that family resources
were not significant predictors for QoL among patients with childhood cancer.
Furthermore, they stated that the potential negative impact of lower family
education, income, employment, and function may be indirect and dynamic over
time.

Study
limitations

The
contributions of this investigation must be considered within the following
limitations: Low participation of female adolescents with SCD could be
explained while considering the socio-cultural and the disease associated
stigma that may force females to refrain from participation due to fear from
disclosure. In addition most adolescent females with SCD seeking care at other
facilities 'private sector' where confidentiality is maintained. We drew our
population especially the control group, from a non-probability sample, which
may have biased our results with subsequent impact on their generalizability.

Conclusions

Adolescents
with SCD experience health related quality of life worse along several domains
of HRQOL including physical functioning, role physical, bodily pain and general
health compared to their comparison group of apparently healthy adolescents.
Socio-demographics including older age of the adolescents with SCD, female
gender, rural residence, low family income and the occurrence of
disease-related complications were associated mainly with deterioration of
physical rather than mental health of our sample of adolescents with SCD.

Controlling
of possible modifiable determinants, e.g., disease-related complications and
some socio-demographics that affect the HRQoL among adolescents with SCD might
improve these patients' outcome with smooth transition to adulthood. HRQoL
assessments in adolescents with SCD facilitate doctor–patient communication,
point to areas where patients may experience serious problems during this
transitory phase, can be used as diagnostic tools for follow–up care, and
assessing the efficiency of different treatment modalities.

Competing
interests

The
authors declared they have no competing interests. Also there are no sources of
funding.

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